Cancer is thought to arise through a complex multi-step process that involves several genetic lesions. In order to study the process, scientists have developed more and more sophisticated animal models. The hope is that such models will teach us about the biology of cancer in addition to providing a system in which potential therapies can be tested. Daniel Tenen and colleagues (Harvard Insititute of Medicine) have engineered mice in which the oncogenic BCR-ABL1 fusion gene -- which causes a substantial proportion of human leukaemias -- can be switched on or off at will.
In the presence of the antibiotic tetracycline (given to mice in their drinking water), the oncogenic fusion gene is 'off' and the mice are healthy. When tetracycline is withdrawn (and thus the fusion gene switched on), the animals develop leukaemia and die within a few weeks. But by putting tetracycline back into the water -- and thus suppressing the fusion gene -- the researchers could achieve complete remission of the leukaemia. These results suggest that the initial oncogenic event (in this case, an overdose of BCR-ABL1) is necessary both to induce and, at least for some time thereafter, to maintain the cancer. Reversal of a single genetic event may therefore have therapeutic value, especially at early stages of the disease.
In addition, these and other mice with 'inducible cancer' enable the study of additional genetic alterations that occur when a normal cell becomes cancerous and eventually metastatic.
Reversibility of acute B-cell leukaemia induced by BCR–ABL1pp 57 - 60 Claudia S. Huettner, Pu Zhang, Richard A. Van Etten & Daniel G. Tenen1
doi:10.1038/71691 Abstract|Full
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Viruses can be used as vectors to deliver therapeutic genes to defective cells. One problem, however, is that many viruses only infect cells that are actively dividing, so they cannot be used to correct defects in cells that no longer proliferate, such as nerve and liver cells. The development of vectors based on lentiviruses -- such as human immunodeficiency virus (HIV) -- instilled much optimism about gene therapy, because these vectors are able to infect non-dividing cells.
But Mark Kay (Stanford University) and colleagues now report that lentiviruses cannot efficiently promote expression of foreign genes in liver cells unless these cells are first induced to proliferate. These findings will dismay researchers developing lentiviruses as gene-therapy tools, because they indicate that lentiviral vectors will not be able to deliver therapeutic genes to non-proliferating organs such as the liver, which is a common target for correcting genetic and metabolic diseases. Kay and colleagues also show that high doses of lentivirus cause liver damage, which means that the vectors may cause more harm than good in patients that already have compromised liver function.
Whereas these findings will disappoint gene therapists, Michael Emerman (Fred Hutchinson Cancer Research Center) explains in accompanying News & Views article how this study enhances our understanding of lentivirus biology. It suggests that there are as-yet-unidentified factors that make non-dividing cells receptive to lentiviral infection without stimulating them to divide. If true, this would have implications for both gene therapy and diseases caused by lentiviruses, including AIDS.
Efficient lentiviral transduction of liver requires cell cycling in vivopp 49 - 52 Frank Park, Kazuo Ohashi, Winnie Chiu, Luigi Naldini & Mark A. Kay1 doi:10.1038/71673 Abstract|Full
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Learning from lentivirusespp 8 - 9 Michael Emerman doi:10.1038/ng0202-130 Abstract|Full
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Hailey-Hailey disease (HHD) is characterized by blisters and erosions of the skin. Ervin Epstein (University of California) and colleagues report that the disease is caused by mutations in the gene ATP2C1, which encodes a pump that transports calcium into the Golgi, a cellular compartment where proteins destined to be secreted are processed. Calcium is critical for normal growth, differentiation and attachment of skin cells. People with HHD have abnormal calcium levels in their skin cells, which weakens the connections between cells, leading to blisters. HHD is the second dermatological disorder caused by defects in calcium metabolism: patients with Darier-White disease develop foul-smelling scaly bumps resulting from defects in a different calcium pump. These findings underscore that finely tuned levels of calcium are needed for healthy skin and may reveal clues for developing treatments for these and other related skin disorders.
Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey diseasepp 61 - 65 Zhilan Hu, Jeannette M. Bonifas, Jenna Beech, Graham Bench, Takako Shigihara, Hideoki Ogawa, Shigaku Ikeda, Theodora Mauro & Ervin H. Epstein Jr doi:10.1038/71701 Abstract|Full
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A flawless replication machinery that preserves the precise sequence of DNA is required for cellular function and genetic inheritance. No system is perfect, though, and errors occur during DNA replication -- these would lead to heritable mutations if it weren't for DNA repair proteins that scan newly synthesized DNA strands and fix the vast majority of mistakes. A group of repair proteins, the MLH and MSH factors, pair with each other in different combinations, and different such pairs correct different types of DNA damage. But sometimes mistakes occur in the genes encoding the repair proteins themselves, resulting in an accumulation of mutations throughout the genome which leads to cancer. Francis Collins (National Human Genome Research Institute) and colleagues have discovered a new DNA repair factor, called MLH3, which pairs with a known repair protein, MLH1. Defects in MLH1 cause colon cancer, raising the possibility that mutations in the gene encoding MLH3 could have similar consequences and may be responsible for colon cancer cases for which the genetic basis is unknown. Josef Jiricny (University of Zurich) discusses in an accompanying News & Views article how these findings affect our understanding of the complex network of 'molecular copy editors' that ensure exact copying of 6 billion base pairs every time a cell divides.
MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instabilitypp 27 - 35 Steven M. Lipkin, Victoria Wang, Russell Jacoby, Sharmila Banerjee-Basu, Andreas D. Baxevanis, Henry T. Lynch, Rosemary M. Elliott & Francis S. Collins
doi:10.1038/71643 Abstract|Full
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